New thioxanthones



United States Patent 2,913,458 NEW THIOXANTHONES Jean Druey, Riehen, andKonrad Meier, Basel, Switzerland, assiguors to Ciba PharmaceuticalProducts Inc., Summit, NJ.

No Drawing. Application October 17, 1957 Serial No. 690,608

7 Claims priority, application Switzerland August 19, 1955 12 Claims.(Cl. 260-2471) This invention relates to new thioxanthones. Moreparticularly the invention concerns 1-aza-2-lower alkyl- 6 (tertiaryamino lower alkylamino) 9 methyl thioxanthones, containing at most onefurther substituent in the thioxanthone ring, said substituent being amethyl group in 4-position, and salts thereof. The tertiary amino groupis preferably an amino group disubstituted by lower alkyl or hydroxalkylgroups, e.g. the dimethylamino, diethylamino, dibutylamino or hydroxyethyl-butylamino group, or a pyrrolidino, piperidino or morpholinogroup. Lower alkyl groups are for example methyl, ethyl, propyl orbutyl. A specific group of compounds of the invention are thel-aza-2-lower alkyl-6-di-loweralkylamino-loweralkylamino-9-methyl-thioxanthones such as 1 aza 2 lower alkyl 6diethylaminoethylamino 9-methyl-thioxanthones, and more particularly1-aza-2- methyl 6 diethylamino ethylamino 9 methyl thioxanthone, and thetherapeutically useful acid addition salts thereof. However, thepreferred embodiment of the invention are the1-aza-2,4,9-trimethyl-6-di-lower alkylamino-loweralkylamino-thioxanthones, and of this group the specific compoundl-aza-2,4,9-trimethyl-6-diethylaminoethylamino-thioxanthone, and thetherapeutically useful acid addition salts of these compounds.

. The new compounds exhibit a pronounced effect against Schistosoma andAmoebae and can be applied as medicaments in cases of humanschistosomiasis and amoebiasis. Compared with the known1-aza-6-diethylaminoethylamino-9-methyl-thioxanthone, they possessespecially valuable properties.

The new compounds are obtained when 1-aza-2-loweralkyl-6-chloro-9-methyl-thioxanthones containing at most one furthersubstituent in the thioxanthone ring, said substituent being a methylgroup in 4-position are reacted with (tertiary amino)-lower alkylamines,as for example diethylamino-ethylamino.

The reaction is carried out in a manner known per se in the presence orabsence of diluents and/ or condensing agents and/0r catalysts,preferably at elevated temperature.

A specific and preferred embodiment of the invention consists in heating1-aza-2,4,9-trimethyl-6-chloro-thioxanthone with an excess ofdiethylamino-ethylamino, distilling off the excess of the amine,dissolving the residue in aqueous acetic acid, rendering the acidsolution alkaline and extracting it with methylene chloride from whichafter washing with water and evaporation 1 aza 2,4,9 trimethyl 6diethylamino ethylamino thioxanthone is obtained.

Depending on the method of working, the new compounds are obtained inthe form of the bases or correspending salts. From the salts, in themanner known per se, the free amine bases can be prepared. Conversely,from the latter, by reaction with acids suitable for the formation oftherapeutically useful acid addition salts, salts can be produced, asfor example those of the hydrohalic acids, sulfuric acid, nitric acid,phosphoric acid,

ice

thiocyanic acid, acetic acid, propionic acid, oxalic acid, malonic acid,succinic acid, malic acid, methane sulfonic acid, ethane sulfonic acid,hydroxy ethane sulfonic acid,

'benzene or toluene sulfonic acid or therapeutically active acids.

Those starting materials which are new can be prepared by conventionalmethods.

The new compounds can be applied as medicaments for example in the formof pharmaceutical preparations which contain them or their salts inadmixture with a pharmaceutical organic or inorganic, solid or liquidcarrier material suitable for enteral, or parenteral administration. Forthe formation of such preparations such other substances are concernedas do not react with the new compounds, as for example water, gelatine,lactose, starch, magnesium stearate, talcum, vegetable oils, benzylalcohols, gums, polyalkylene glycols, petroleum jelly, cholesterol orother known medicament carriers. The pharmaceutical preparations can bemade up, for example, in the form of tablets, dragees, or in liquid formas solutions, suspensions or emulsions. If desired they are sterilizedand/or may contain auxiliary substances such as preservative,stabilizing, wetting or emulsifying agents, salts for v2 rying theosmotic pressure or bufier substances. They can also. contain othertherapeutically valuable substances. The preparations are obtained according to customary methods.

This application is a continuation-in-part of our copending applicationsSerial No. 605,227, filed August 20, 1956 and Serial No. 629,245, filedDecember 19, 1956, both now abandoned.

The following examples illustrate the invention:

Example 1 13.8 grams of 1-aza-2:9-dimethyl-6-chloro-thioxanthone in 60cc. of diethylaminoethylamine are heated under gentle reflux for 5 hoursat 160 C. The excess of the diamine is then distilled OE and the residuetreated with cc. of 10 percent acetic acid. The solution is extracted byshaking with a little ether, separated from theether and afterfiltration over charcoal, rendered basic with potassium carbonate. Thefree base is extracted with ether., After washing with water andevaporation, the ether solution leaves as residue the yellow,crystalline base. aminoethylarnino-9-methyl-thioxanthone of the formula1 \*H-oH.-oH.'N(o.H.)|

CH N

yellow needles of melting point 229,-2295" C. :Q'gx.

From alcohol 1-aza-2-methyl-6-diethyl-v The1-aza-2,9-dimethyl-fi-chloro-thioxanthone can he prepared in thefollowing manner:

64 grams of 2-chloro-3-cyano-6-methyl-pyridine are boiled under refluxfor 16 hours with 83.5 grams of the dry sodium compound of2-methyl-5-chloro-thiophenol in 500 cc. of dioxane. The product isfiltered from common salt, the residue after evaporating dissolved inmethylene chloride and the solution washed with water, dried andevaporated. The residue consisting of 6- 'methyl 3 cyano 2 (5 chloro 2'methyl phenylthiol) pyridine of melting point 110-111 C. isrecrystallized from methanol. Yield 98 grams.

27.45 grams of the nitrile are heated for 12 hours to 140-150 C.- in 200cc. of 80 percent sulfuric acid. The product is then poured on ice,adjusted to pH 3 with 10 N-caustic soda solution and extracted withmethylene chloride. On distilling oif the methylene chloride thereremains crystalline 6-methyl-3-carboxy-2-(5-chloro-2'-methylphenylthiol)-pyridine of melting point 167-169" C. Yield 24grams.

29.35 grams of this carboxylic acid in 150 cc. of concentrated sulfuricacid are heated for 2 hours to 140-150 C. The product is then poured onice, rendered alkaline with 10 N-caustic soda solution and extractedwith methylene chloride. The residue obtained after distilling off themethylene chloride is recrystallized from dioxane. The1-aza-2,9-dimethyl-6-chloro-thioxanthone melts at 204-206 C. Yield 21.4grams.

Example 2 CH. I

melts at 88 C. The yield is 15 grams.

To prepare the hydrochloride, the base is dissolved in alcohol mixedwith the calculated quantity of alcoholic hydrochloric acid, and thesolution concentrated. The hydrochloride crystallizes in the form ofgolden yellow matted needles of melting point 195-196 C.

The l-aza 2 isobutyl-6-chloro-9-methyl-thioxanthone used as startingmaterial can be obtained in the following manner:

19.45 grams of 2-chloro-3-cyano-6-isobutyl pyridine are boiled underreflux for 20 hours with 18.8 grams of the sodium compound of2methyl-5-chloro-thiophenol in 300 cc. of absolute toluene. Water isthen admixed, the toluene solution separated, washed with 2 N-causticsoda solution and water, and the toluene distilled off. The 6 isobutyl 3cyano 2 chloro 2' methylphenyl-thiol)-pyridine distills at 158 C. under0.09 mm. pressure of mercury to give a nearly colorless oil. The yieldis 16.5 grams.

15.8 grams of this nitrile are heated to 140-150 C. for 5 hours with 150cc. of sulfuric acid of 80 percent strength. The mixture is then pouredon to ice, given a pH of 3-4 with concentrated ammonia while beingcooled with ice, and the precipitated carboxylic acid filtered ofi withsuction. For purification it is dissolved while warm in dilute excesssodium bicarbonate solu- 4 tion, the solution filtered with charcoal,and the acid precipitated again with 2 N-hydrochloric acid. In thismanner there are obtained 15.1 grams of crude 6-isobutyl- 3 carboxy 2 (5chloro 2 methyl phenylthi0l)-pyridine. After repeated recrystallationfrom dilute alcohol, the pure product melts at l57158 C.

14 grams of this carboxylic acid are heated to C. for 5 hours with 300grams of polyphosphoric acid. The mixture is then poured onto ice andthe reaction product extracted with methylene chloride. The methylenechloride solution is washed with dilute caustic soda solution and waterand evaporated. There remain behind 13.25 grams of1-aza-2-isobutyl-6-chloro-9-meth yl-thioxanthone in the form of abrownish oil which crystallizes slowly. The product is used withoutfurther purification.

Example 3 melts at 95-96" C. when recrystallized from acetone. Thehydrochloride obtained in the usual manner melts at 226-228 C. Yield:7.3 grams.

Example 4 6.88 grams of 1-aza-2,9-dimethyl-6-chlorothioxanthone areboiled under reflux with 50 cc. of morpholino-ethylamine for 12 hours.After distilling olf the excess base, the residue is dissolved, hot in200 cc. of acetic acid of 10% strength, the solution is filtered withcarbon and, after cooling, the base is precipitated with ice-cooling andstirring by the addition of dilute caustic soda solution in the form ofcrystals. The precipitate is suction-filtered, washed neutral with waterand dried in vacuo. The 1-aza-2,9-dimethyl-6-morpholino-ethylamino-thioxanthone of the formulaNH-CHrCHr-N b l \NLS melts at 1355-1365 C. when recrystallized fromacetone.

The hydrochloride prepared in the usual manner crystallizes from amixture of water and acetone in the form of yellow, matted needlesmelting at 280-282 C. Yield:

6 grams.

' Example 5 9 grams of 1-aza-2,4,9-trimethyl-6-chlorothioxanthone areboiled under reflux in 40 cc. of diethylarninoethylamine for 5 hours atC. The excess of the diamine is distilled off under vacuum, the residuedissolved in 200 cc. of 10% acetic acid, the solution filtered overCelite" (registered trademark) and the filtrate rendered alkaline withammonia.

crystallizes in golden yellow fine leaflets of melting point 118-118.5C. 1

The hydrochloride, prepared in the customary manner, forms orange yellowprisms of melting point 228229 C.

The 1-aza-2,4,9-trimethyl-6-chloro-thioxanthone used as startingmaterial can be prepared in the following manner:

33 grams of 2-chloro-3-cyano-4,6-dimethyl-pyridine with the dry sodiumcompound from 31.7 grams of 2- methyl-5-chloro-thiophenol are boiledunder reflux for 10 hours in 150 cc. of absolute dioxane, with stirring,in a nitrogen atmosphere. Filtration with suction over Celite from thecommon salt formed is then carried out, the filtrate then evaporated andthe residue taken up in methylene chloride. The methylene chloridesolution is washed with dilute caustic soda solution and water, dried,evaporated and the residue recrystallized from methanol. The 4,6dimethyl ,3 cyano 2 (5' chloro 2' methyl-phenylmercapto)-pyridine meltsat 101102 C. Yield 48 grams.

28.35 grams of the nitrile are heated with stirring for 6 hours to140-150 C. in 250 cc. of 80% sulfuric acid. The whole is then cooled to-l0 C. and a concentrated aqueous solution of 10 grams of sodium nitriteadded dropwise beneath the surface of the liquid with stirring. Thefreezing mixture is then removed and after the reaction mixture hasattained room temperature it isheated in 1 hour to 50-60 C. Stirring iscontinued for about 2 hours longer at this temperature until theevolution of gas is complete. The mixture is now poured on ice, broughtto pH 4 with concentrated ammonia and the carboxylicacid produced as ayellowish plastic mass is filtered oif. It is dissolved with heating indilute sodium carbonate solution and the solution filtered oil from anyinsoluble secondary product and reprecipitated with acetic acid. The4,6-dimethyl-3-carboxy-2-(5'-chloro-2'- methylphenylmercapto) pyridine,when recrystallized from dilute alcohol melts at 155-156 C.- Yield 22.45grams.

22 grams of this carboxylic acid are heated for 6 hours to 160-170 C. in400 grams of polyphosphoric acid. The melt is poured on ice and renderedalkaline with concentrated ammonia with cooling and the precipitatedproduct produced by ring closure is taken up in methyllene chloride. The1-aza-2,4,9-trimethyl-6-chloro-thioxanthone is recrystallized from amixture of dioxane and alcohol and forms yellowish leaflets of meltingpoint 162 163 C. Yield 18.3 grams.

Example 6 grams of 1-aza-2,4,9-trimethyl-6-chloro-thioxanthone arerefluxed for 5 hours with 30 cc. of 'y-diethylaminopropylamine. Theexcess diamine is distilled off in vacuo and the residue heated with 200cc. of 10% acetic acid, the solution filtered with suction throughCelite to remove some insoluble by-product, and the orange-yellowfiltrate rendered alkaline with 2 N-caustic soda solution.

The base which precipitates is taken up in ether, the ethereal solutionwashed with water, dried with sodium sulfate, and evaporated. Theremaining brown-red oil (5.6 grams) crystallizes slowly and isrecrystallized from a mixture of ether and petroleum ether. The yield iss 4.5 grams. The resulting.1aza-2,4,9-trimethyl-6-diethylaminopropyIamino-thioxanthone of theformula 0H, 0 NH-cm-om-oHr-N melts at 62-63 C. Its hydrochloride,obtained in the usual manner, melts at 23 5236 C.

Example 7 5 grams of 1-aza-2,4,9-trimethyl-6-chloro-thioxanthone areheated to 180 C. in an oil bath for 6 hours with 10 cc. of N-(fi-arninoethyl)-morpholine. The mixture is dissolved while warm in 30cc. of glacial acetic acid, and the solution'diluted with 270 cc. of hotwater while being shaken. An undissolved by-product is then removed byfiltering with suction through Celite, and the clear yellow-red filtraterendered Weakly alkaline with 2 N-caustic soda solution which is addeddropwise while the filtrate is being stirred and cooled with ice. Thebase which precipitates in the form of crystals is filtered withsuction, washed with water, dried in vacuo, and recrystallized fromalcohol. The resulting1-aza-2,4,9-trimethyl-6-morpholinoethylaminothioxanthone of the formulaExample 8 5 grams of 1-aza-2,4,9-trimethyl-6-chloro-thioxanthone arerefluxed for 6 hours with 25 cc. of dimethylaminoethylamine. Afterworking up as described in Example 7, the base (3.1 grams), precipitatedin crystalline form from the acetic acid solution with the aid of dilutecaustic soda solution, is recrystallized from alcohol. The resulting 1azo 2,4,9 trimethyl 6 dimethylaminoethylammo-thioxanthone of the formulaI I ll CH3 711, o NH-OH,GHT-N a m H l on.

Example 9 9.65 grams of 1-aza-2,4,9trimethyl-6-chloro-thioxanthone areheatedat "-170" C. for 18 hours with 11' grams ofN-butyl-N-(fi-hydroxyethyl)-amino-ethylamine and a'trace of copperpowder. After working up as described in Example 7 the base precipitatedfrom the dilute acetic acid solution by means of caustic soda solutionis taken up in ether, the ethereal solution washed with water, dried andevaporated. The residue (6.3 grams of crystalline base) isrecrystallized from a mixture of ether and petroleum ether. Theresulting 7 1 aza 2,4,9 trimethyl 6 [(N 8- hydroxyethyl N- butyl-amino)-ethylamino] -thioxanthone of the formula forms fine yellow needles ofmelting point 109110 C. The hydrochloride, after recrystallization froma mixture of alcohol and ether, melts at 137 C. It contains 1 mol ofcrystal water.

Example 10 grams of 1-aza-2,4,9-trimethyl-6-chloro-thioxanthone areheated to 160-470 C. for hours with 10 grams ofdi-n-butylamino-ethylamine. The mixture is then heated on the water bathwith 100 cc. of 2 N-hydrochloric acid, some insoluble matter is removed,and the yellowred, acid filtrate rendered alkaline with potassiumcarbonate. The base, which precipitates in the form of a brown-redviscous oil, is filtered with suction, taken up in ether, the etherealsolution washed several times with water, dried and evaporated. Theresidual brown-red oil crystallizes on the addition of acetone in theform of yellow needles of melting point 60-63 C. The base is dissolvedin acetone, the calculated quantity of 1 N-hydrochloric acid is addedand the deep red solution evaporated to complete dryness. The residue isdissolved in absolute, hot alcohol, the solution considerablyconcentrated and then mixed with absolute ether until crystallizationsets in. The hydrochloride of1-aza-2,4,9-trimethyl-6-dibutylannnoethylamino-thioxanthone of theformula 0 (fl) 2 \(CHMH on crystallizes in the form of orange yellowprisms of melting point 2ll2l3 C. The yield is 4.8 grams.

Example 11 5 grams of 1-aza-2,4,9-trimethyl-6-chloro-thioxanthone areheated at 160 C. for hours with 13 grams of l- .[N ethyl N (phydroxyethyl) amino] propyl 2- amine. The reaction mixture is worked upas in Example 10. The base, which is obtained in crystalline formdirectly from the ethereal solution, is recrystallized from acetone. Thegolden yellow 1-aza-2,4,9-trimethyl-6- fl (N ethyl N 5 hydroxyethylamino) propyl- (2)-amino]-thioxanthone of the formula (11H; C1115 (11H;NH-CH-CHr-N C CZHQOH thus obtained melts at 103-105 C.

The hydrochloride prepared in the usual manner melts at 198-199 C.

What is claimed is: I

1. A 1-aza-2-lower alkyl-6(tertiary amino-loweralkylamino)-9-rnethyl-thioxanthone containing at mostone furthersubstituent in the thioxanthone ring, said substituent being a methylgroup in 4-position, the tertiary-amino group of which is selected fromthe group consisting of amino groups disubstituted by members selectedfrom the group consisting of lower alkyl and lower hydroxyalkyl groupsand pyrrolidino-, piperidino-, and morpholino groups, andtherapeutically useful acid addition salts thereof.

2. Compounds of the formula wherein R stands for a lower alkyl group, Xrepresents a lower alkylene radical and B a di-lower alkyl-arnino group,and therapeutically useful acid addition salts thereof.

3. Compounds of the formula wherein X represents a lower alkyleneradical and B a di-lower alkyl-amino group, and therapeutically usefulin which R represents lower alkyl.

References Cited in the file of this patent UNITED STATES PATENTS2,627,518 Archer Feb. 3, 1953 2,653,949 Archer Sept. 29, 1953 2,653,950Archer Sept. .29, 1953 2,653,951 Archer Sept. 29, 1953 2,691,657 CoornbsOct. 12, 1954

1. A 1-AZA-2-LOWER ALKYL-6-(TETTIARY AMINO-LOWERALKYLAMINO)-9-METHYL-THIOXANTHONE CONTAINING AT MOST ONE FURTHERSUBSTITUENT IN THE THIOXANTHRONE RING, SAID SUBSTITUENT BEING A METHYLGROUP IN 4-POSITION, THE TERTIARY-AMINO GROUP OF WHICH IS SELECTED FROMTHE GROUP CONSISTING OF AMINO GROUPS DISUBSTITUTED BY MEMBERS SELECTEDFROM THE GROUP CONSISTING OF LOWER ALKYL AND LOWER HYDROXYALKYL GROUPSAND PYRROLIDINO-, PIPERIDINO-, AND MORPHOLINO GROUPS, ANDTHERAPEUTICALLY USEFUL ACID ADDITION SALTS THEREOF.
 8. 1 - AZA - 2,9 -DIMETHYL - 6 - MORPHOLINO-ETHYLAMINOTHIOXANTHONE.